Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.

Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer.

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

Effect of ambient temperatures ranging from cold to heat on thermoregulation in conscious MK801-treated rats.

The glutamate NMDA receptor has been suggested to be involved in thermoregulation. To further analyse its role, the thermoregulatory responses of rats treated with 0.5 mg.kg-1 of dizocilpine (MK801) were compared with those of control rats treated only with the same volume of saline during a 180-min exposure at one of the six different ambient temperatures, ranging from cold to heat. Colonic temperature (Tco) and tail skin temperature (Ttail) were measured throughout using Cu-Ct thermocouples. In the cold (2.4 and 12.3 degrees C), Tco decreased either sharply (MK801) or progressively (saline), reaching the same final value (2.4 degrees C) or a lower value in the MK801-treated rats (12.3 degrees C). At the same time, Ttail decreased in both groups. In the cool environment (20.7 degrees C), Tco and Ttail decreased in both groups, with lower final values in MK801-treated rats. At thermoneutrality (28.8 degrees C), the MK801-induced hyperthermia remained steady, while Ttail increased in both groups. In the heat (34.6 and 36.2 degrees C), Tco and Ttail increased in both groups, with higher final values in MK801-treated rats. Moreover, at 36.2 degrees C, only MK801-treated rats exhibited heatstroke. It is thus suggested that MK801-induced inhibition of NMDA receptors impairs thermoregulation, especially in the heat.

Positive end expiratory pressure (PEEP) slightly modifies ventilatory response during incremental exercise.

To clarify the ventilatory effects of a 5-cm H2O positive end expiratory pressure (PEEP) in healthy men during incremental exercise in normoxic conditions, 22 subjects were subjected to a constant workload (0 W, 50 W, 100 W, 150 W and 200 W) on a cycle ergometer for periods of 8 min each, both with and without 5-cm H2O PEEP. Results show that PEEP increases inspiratory (TI) and expiratory (TE) duration and tidal volume (VT) and decreases breathing frequency (fB) at rest (p < 0.05). During exercise, TI is higher at 50 W and 100 W (p < 0.05), but not at 150 and 200 W. TE only increases at 50 W (p < 0.05). An increased VT (p < 0.05 at 50, 100 and 150 W) and a decreased fB (p < 0.05 throughout the experiment) were observed. However, mean inspiratory flow (VT/T1) and duty cycle (TI/TT) were unaffected by PEEP. In conclusion, this study shows that a 5-cm H2O PEEP slightly modifies the ventilatory parameters in healthy subjects during incremental exercise in normoxic conditions.

Positive expiratory pressure as a method for preventing the impairment of attentional processes by hypoxia.

This study investigated the effects of hypoxia on parallel/preattentional and serial/attentional processes in early vision, and the use of a positive-end-expiratory-pressure (PEEP) to prevent the impairment in performance. Twenty-one subjects were submitted to an 8-h hypoxia exposure in a hypobaric chamber (4500 m, 589 hPa, 22 degrees C), both with and without a 5-cm H2O PEEP. Subjects carried out a visual search task consisting of detecting a target among distractors in normoxia, in acute and in prolonged hypoxia. Conjointly their sensitivity to acute mountain sickness (AMS) was scored through the Lake Louise AMS scoring system. Results showed that prolonged hypoxia slowed serial/attentional processing whereas parallel/preattentional processes were not impaired either by acute or by prolonged hypoxia. PEEP prevented serial/attentional processes from slowing and those effects were more clearly observed in the AMS sensitive subjects with respect to the AMS insensitive subjects. These results suggest that the slowing induced by prolonged hypoxia is specific to an early visual process that pilots the scanning of an attentional spotlight throughout the visual field.

Determination of the velocity associated with VO2max.

PURPOSE: The theoretical velocity associated with VO2max (vVO2max) defined by Daniels (1985) is extrapolated from the submaximal VO2-velocity relationship. VO2 is generally determined by assuming that the aerobic response reacts like a linear first-order system at the beginning of square-wave exercise with a steady-state reached by the 4th minute. However, at supra-ventilatory threshold work rates, the steady state in VO2 is delayed or not attained. METHODS: The present study was carried out to compare three values for vVO2max determined with Daniels' method, but with VO2 either measured at the 4th minute (vVO2max4), the 6th minute (vVO2max6), or after the attainment of the true steady-state (vVO2maxSS). The metabolic response during square-wave exercise at each of the three vVO2max were also assessed. RESULTS: These velocities were significantly different (P < 0.05), but vVOmaxSS and vVO2max6 were highly correlated (r = 0.98; P < 0.05). Blood lactate concentrations measured after exercise at velocities very close to the three vVO2max were similar and the end-exercise VO2 were not different from VO2max, but the time required to elicit 95% VO2max during these three square-wave tests were significantly different. CONCLUSION: Therefore, when vVO2max is determined by extrapolation from the submaximal VO2-velocity relationships, submaximal VO2 should be measured beyond the 6th minute of square-wave exercise (at least if it takes 30 s to reach the desired velocity) to ensure that all vVO2max reported in future studies describe a similar quantitative index.

Sympathetic stimulation induced by hand cooling alters cold-induced vasodilatation in humans.

Hand cooling is a cold pressor test, which induces general sympathetic stimulation. This cooling procedure is often performed to investigate cold induced vasodilatation (CIVD) in one finger. To investigate the effects of this sympathetic stimulation on local CIVD, 12 subjects immersed either the right index finger (T1), right hand (T2) or left hand and right index finger (T3) for 30 min in water at 5 degrees C followed by 15-min recovery. Skin temperature and skin blood flow (Q(sk)) measured by laser Doppler flowmetry on the right index finger, as well as heart rate (f(c)) and mean arterial blood pressure (BP(a)), were continuously monitored during the three tests. Cutaneous vascular conductance was calculated as Q(sk)/(BP(a)). Concentrations of plasma noradrenaline (NA) and adrenaline (AD) were measured at different times during the tests. The results showed no cardiovascular change in T1, whereas f(c) and (BP(a)) increased significantly at the beginning of both T2 and T3. Similarly, sympathetic stimulation was reflected in the NA concentrations, which increased significantly (P < 0.01) during T2 and T3 after 5 min of immersion, and remained elevated until the recovery period. The AD concentration did not change during the three tests. During T2, the CIVD appeared later and slower in comparison with T1 [CIVD onset: 12.81 (SEM 2.30) min in T2 and 5.62 (SEM 0.33) min in T1]. During T3, the CIVD onset was not delayed compared to T1 [6.38 (SEM 0.67) min], but the rewarming was lower [+5.40 (SEM 0.86) degrees C in T3 and +9.10 (SEM 1.31) degrees C in T1]. These results showed that CIVD could be altered by sympathetic stimulation but it also appeared that the onset of CIVD could be influenced by local cooling, independently of the general sympathetic stimulation.

Short hypobaric hypoxia and breathing pattern: effect of positive end expiratory pressure.

The ventilatory effects of a 5-cm H2O positive end expiratory pressure (PEEP) and its influence on the breathing pattern during short hypoxic exposure both at rest and during physical exercise were studied. There were 22 healthy subjects who were submitted to normoxia and to 4-h of hypoxia in a hypobaric chamber (4500 m, PB = 589 hPa) both at rest and during an 8-min cycle ergometer exercise (100 W) without and with a 5 cm H2O PEEP. The results show that hypoxia compared with normoxia induces increases in tidal volume (VT) (+28.5%, p < 0.05 at rest; and +19.4%, p < 0.01 at 100 W) and in respiratory frequency (f) at 100 W (p < 0.05), and significant decreases in inspiratory (tI) (p < 0.05 at rest and at 100 W), and expiratory (tE) durations (p < 0.05 at 100 W). However, the breathing pattern expressed as duty cycle (tI/tt) is unchanged, whereas an increased mean inspiratory flow (VT/tI) is observed (p < 0.01 at rest and at 100 W). This study also demonstrates that PEEP during a 4-h hypobaric hypoxia significantly increases VT (+22.2% p < 0.01 at rest, +8.9% p < 0.05 at 100 W), tI, and tE at rest (p < 0.05), but not during exercise and tends to decrease f (p = 0.06 at rest and at 100 W). However, PEEP does not alter the breathing pattern in hypoxia since VT/tI and tI/tt are unchanged. Heart rate and arterial O2 saturation are also unaffected by PEEP. In conclusion, this study shows that a 4-h hypoxia modifies ventilatory parameters and mean inspiratory flow (VT/tI) at rest and during exercise (100 W), whereas a 5-cm H2O PEEP does not alter the breathing pattern despite changes in ventilatory parameters are observed.

Effects of acute hypobaric hypoxia on the appearance of ingested deuterium from a deuterium oxide-labelled carbohydrate beverage in body fluids of humans during prolonged cycling exercise.

To determine whether or not acute hypobaric hypoxia alters the rate of water absorption from a carbohydrate beverage ingested during exercise, six men cycled for 80 min on three randomly assigned different occasions. In one trial, exercise was performed in hypoxia (barometric pressure, P(B) = 594 hPa, altitude 4,400 m) at an exercise intensity selected to elicit 75% of the individual's maximal oxygen uptake (VO2max) previously determined in such conditions. In the two other experiments, the subjects cycled in normoxia (P(B) = 992 hPa) at the same absolute and the same relative intensities as in hypoxia, which corresponded to 55% and 75%, respectively, of their VO2max determined in normoxia. The subjects consumed 400 ml of a 12.5% glucose beverage just prior to exercise, and 250 ml of the same drink at 20, 40 and 60 min from the beginning of exercise. The first drink contained 20 ml of deuterium oxide to serve as a tracer for the entry of water into body fluids. The heart rate (HR) during exercise was higher in hypoxia than in normoxia at the same absolute exercise intensity, whereas it was similar to HR measured in normoxia at the same relative exercise intensity. Both in normoxia and hypoxia, plasma noradrenaline concentrations were related to the relative exercise intensity up to 40 min of exercise. Beyond that duration, when exercise was performed at the highest absolute power in normoxia, the noradrenaline response was higher than in hypoxia at the same relative exercise intensity. No significant differences were observed among experimental conditions, either in temporal profiles of plasma D accumulation or in elimination of water ingested in sweat. Conversely, elimination in urine of the water ingested appeared to be related to the severity of exercise, either high absolute power or the same relative power combined with hypoxia. We concluded that water absorption into blood after drinking a 12.5% glucose beverage is not altered during cycling exercise in acute hypobaric hypoxia. It is suggested that the elimination of water ingested in sweat and urine may be dependent on local circulatory adjustments during exercise.

Influence of the oxygen uptake slow component on the aerobic energy cost of high-intensity submaximal treadmill running in humans.

During high-intensity running, the oxygen uptake (VO2) kinetics is characterised by a slow component which delays the attainment of the steady-state beyond the 3rd min of exercise. To assess if the aerobic energy cost of running measured at the 3rd min (C3) adequately reflects the variability of the true aerobic energy cost measured during the steady-state (Css), 13 highly-trained runners completed sessions of square-wave running at intensities above 80% maximal oxygen uptake (VO2max) on a level treadmill. To evaluate the time at which the steady-state VO2 was attained (tss), the VO2 responses were described using a general double-exponential equation and tss was defined as the time at which VO2 was less than 1% below the asymptotic value given by the model. All the subjects achieved a steady state for intensities equal to or greater than 92% VO2max, and 8 out of 13 achieved it at 99% VO2max. In all cases, tss was less than 13 min. For intensities greater than 85% VO2max, Css was significantly higher than C3 and was positively related to %VO2 max (r=0.44; P < 0.001) while C3 remained constant. The C3 only explained moderately the variability of Css (0.39 < r2 < 0.72, depending on the velocity or the (relative intensity at which the relationship was calculated). Moreover, the excess aerobic energy cost of running the (difference between Css and C3) was well predicted by age (0.90 < r2 < 0.93). Therefore, when the aerobic profile of runners is evaluated, it is recommended that their running efficiencies at velocities which reflect their race intensities should be determined, with VO2 data being measured at the true steady-state.

Thermoregulatory changes in the cold induced by physical training in humans.

It has previously been demonstrated that metabolic heat production (M) during cold exposure at rest was related to maximal oxygen uptake (VO2max). Consequently, an increase in VO2max could allow an increase M in the cold. The aim of the present study was therefore to test this hypothesis. Eight male volunteers undertook interval training (periods of 25% VO2max of 30-s duration and 110% VO2max of 60-s duration until exhaustion, five times a week over 8 weeks) to increase VO2max. Both before and after this physical training, they were subjected to a 10 degrees, 5 degrees and 1 degrees C 2-h cold air test in a climatic chamber. During the cold exposure, rectal temperature (Tre), tympanic temperature (Tty) mean skin temperature (Tsk) and M were measured as well as the time to onset of shivering (t) and body temperatures (Tre, Try and Tsk) at t. The results showed that physical training involved an increase in VO2max (14%-15%, P < 0.05). During the cold exposure, Tre was higher after training both at 10 degrees, 5 degrees and 1 degree C (P < 0.05) whereas Tty, TSk and M were not significantly changed. However, an increase in the sensitivity of the thermoregulatory system was attested by a decreased t at higher Tsk. These slight physiological changes found after training were not related to the increases in VO2max. In conclusion, this study demonstrated that interval training induced slight thermoregulatory changes unrelated to changes in VO2max and it suggested that M during cold exposure could be related mainly to the level of VO2max observed before training, since increases in VO2max did not modify M.

Positive end expiratory pressure as a method for preventing acute mountain sickness.

In order to study the use of positive end expiratory pressure (PEEP) to prevent acute mountain sickness (AMS), 22 subjects were exposed randomly to 8-h hypobaric hypoxia in a hypobaric chamber (4500 m, 589 hPa, 22 degrees C) once being administered 5-cm H2O PEEP and once without. The prevention of AMS by PEEP was evaluated by scoring AMS according to the Lake Louise system (self-report questionnaire and clinical assessment) throughout the experiment with O2 saturation (SO2) and heart rate measurements being made. Arterial blood analyses (partial pressures of arterial O2 and CO2, PaO2, PaCO2, and pH) were made at the end of the exposure. Results showed decreased AMS scores with PEEP at the end of the 8-h hypoxia [1.50 (SEM 1.32) vs 3.23 (SEM 2.07), P < 0.01 for self-report plus clinical assessment scores] with a lower prevalence (23% vs 55%, P < 0.01). The SO2, PaO2, PaCO2 and HCO3- did not change significantly. However, a smaller increase in arterial pH [7.47 (SEM 0.02) vs 7.50 (SEM 0.02), P < 0.05] was observed with PEEP, attesting a lesser alkalosis. Moreover, heart rate increased with PEEP (P < 0.05). In conclusion, this study would suggest that a 5-cm H2O PEEP may help decrease AMS scores at the end of an 8-h exposure to hypoxia in a hypobaric chamber. Such a method could be used to prevent AMS in such experimental conditions without adverse effects.

Pre-adaptation, adaptation and de-adaptation to high altitude in humans: hormonal and biochemical changes at sea level.

High altitude residence is known to modify body biochemistry and hormone status. However, the effects of such a sojourn on these status observed at sea level both immediately and later after return are not as well established as are the effects of an intermittent acclimation. The aim of this study was therefore to investigate these changes. To achieve our objectives, nine subjects received intermittent acclimation at low pressure in a barometric chamber (8 h daily for 5 days, day 1 at 4500 m, day 5 at 8500 m) before an expedition to the Himalayas. Hormonal and biochemical changes were studied using samples of venous blood taken at sea level before and after acclimation, after return from the expedition and 1 and 2 months after descent. Concentrations of thyroid hormones, adrenaline, noradrenaline (NA), hormones of hydromineral metabolism (aldosterone, renin, arginine vasopressin, atrial natriuretic peptide) as well as prolactin, cortisol, insulin and endothelin 1 were measured. Biochemical measurements made were plasma osmolality, and concentrations of glucose, total cholesterol, total proteins, pre-albumin, transferrin, complement 3C, apolipoproteins A1 and B and serum iron. Acclimation induced no alteration in hormone (except for NA with increases of about 1.5, fold P < 0.05) and biochemistry data. After the expedition, hormone responses were characterized by a higher total triidothyronine concentration (+18%, P < 0.05) while other hormones did not vary. A linear relationship was found between thyroid-stimulating-hormone and body mass changes after the expedition (r = 0.67, P < 0.05). The observed increased concentrations of plasma proteins and total cholesterol (P < 0.05) could be related to the restoration of lean body mass. At 1 and 2 months after return, no changes in hormones were observed but a significant decrease in transferrin concentration was noticed. The higher serum iron concentration reported after 1 month (P < 0.05) could have been the result of a physiological haemolysis. It was concluded that both acclimation and the expedition in the Himalayas affected hormone status and body biochemistry status even though the observed changes were slight and rapidly reversed.

Cognitive performance during short acclimation to severe hypoxia.

BACKGROUND: Exposure to high altitudes requires acclimation or acclimatization, to prevent the negative effects of severe hypoxia. Among several methods, short acclimation with intermittent exposure to severe hypoxia in a hypobaric chamber triggers efficient physiological pre-adaptation mechanisms (11-13). However, we have little knowledge about the cognitive repercussions of such an acclimation protocol. METHODS: Four mountaineers were tested daily in the course of a short acclimation protocol (5 d). After their SaO2 (arterial oxyhemoglogin saturation) were recorded, they carried out a choice reaction time task (Manikin test) twice every day; first at ground level (250 m, control sessions), second at the highest altitude of the day (D1 = 5000 m, D2 = 5500 m, D3 = 6000 m, D4 = 6500 m, D5 = 7000 m). RESULTS: High altitude SaO2 level decreased during the first 3 d, then stabilized around 72-73%. Despite a slight and transient increase at the highest altitude relative to the ground level in D4, the error rate remained low throughout the protocol. Further, response time to the Manikin task did not show significant changes among the days during the acute stage of hypoxia relative to ground level up to 7000 m. CONCLUSIONS: On the whole, it seems that a short acclimation protocol based on intermittent exposure to simulated high altitudes triggered adaptive processes without major impairment in a choice reaction time task during the acute stages of severe hypoxia.

Are the laboratory and field conditions observations of acute mountain sickness related?

In order to study relationships between acute mountain sickness (AMS) observations done both during a short-term hypoxic exposure in a hypobaric chamber, and in field conditions during a high altitude expedition, nine subjects were submitted to a 9-h hypoxic exposure in a hypobaric chamber. Then, they experienced a high altitude expedition in the Himalayas. The Lake Louise AMS scoring system was used to assess AMS in both conditions, especially the self report questionnaire. During the expedition, the mean self report score of each subject, defined as the ratio between the sum of daily self report scores and the duration of the expedition, appears to be correlated not only to the maximal self report score observed in altitude (r = +0.77, p < 0.05) but also to the self report and self report+clinical assessment scores observed at the end of the hypobaric chamber sojourn (r = +0.81, p < 0.01 and r = +0.75, p < 0.05, respectively). In conclusion, the Lake Louise AMS scoring system, especially the self report questionnaire, is relevant to assess AMS with simplicity and rapidity both in laboratory and in field conditions. Our study also suggests that AMS induced by a short term sojourn in a hypobaric chamber is related to AMS observed in field conditions.

Effects of various beverages on the hormones involved in energy metabolism during exercise in the heat in previously dehydrated subjects.

The objective of our study was to examine the effects of beverage content on hormone responses involved in fuel substrate metabolism (catecholamines, insulin and glucagon) in previously dehydrated subjects exercising at a moderate intensity in the heat. Six healthy men walked for 60-min on five occasions at 50% maximal oxygen uptake in a warm environment (dry bulb temperature 35 +/- 0.2 degrees C, relative humidity 20%). On each occasion, the subjects were dehydrated before exercise (loss of 2% body mass) by passive controlled hyperthermia, which led to a reduction in plasma volume (PV) of about -5% to -9%. In one session, the subjects exercised without rehydration (Dh). In the other sessions, four beverages (650 ml) were given just before the exercise: mineral water (W), a 60 g x l(-1) glucose and 1.2 g x l(-1) NaCl solution (GS), a 60 g x l(-1) maltodextrin solution, and a 60 g x l(-1) maltodextrin and 1.2 g x l(-1) NaCl solution. Compared to Dh and W, carbohydrate supply with or without NaCl induced a higher glycaemia (P < 0.05), a reduced increase in plasma adrenaline concentration (P < 0.05) and a higher plasma insulin concentration (P < 0.05), which lowered plasma free fatty acids and glycerol concentrations (P < 0.05). The lesser increase in plasma noradrenaline concentrations observed during GS compared to Dh and W sessions can be explained by a larger correction in PV which might have induced better haemodynamic conditions. However, the increase in plasma glucagon with carbohydrate supply--compared to Dh and W (P < 0.05)--remains unexplained.

Cold induced vasodilatation and cardiovascular responses in humans during cold water immersion of various upper limb areas.

To study the physiological responses induced by immersing in cold water various areas of the upper limb, 20 subjects immersed either the index finger (T1), hand (T2) or forearm and hand (T3) for 30 min in 5 degrees C water followed by a 15-min recovery period. Skin temperature of the index finger, skin blood flow (Qsk) measured by laser Doppler flowmetry, as well as heart rate (HR) and mean arterial blood pressure (BPa) were all monitored during the test. Cutaneous vascular conductance (CVC) was calculated as Qak/BPa. Cold induced vasodilatation (CIVD) indices were calculated from index finger skin temperature and CVC time courses. The results showed that no differences in temperature, CVC or cardiovascular changes were observed between T2 and T3. During T1, CIVD appeared earlier compared to T2 and T3 [5.90 (SEM 0.32) min in T1 vs 7.95 (SEM 0.86) min in T2 and 9.26 (SEM 0.78) min in T3, P < 0.01]. The HR was unchanged in T1 whereas it increased significantly at the beginning of T2 and T3 [+13 (SEM 2) beats.min-1 in T2 and +15 (SEM 3) beats.min-1 in T3, P < 0.01] and then decreased at the end of the immersion [-12 (SEM 3) beats.min-1 in T2, and -15 (SEM 3) beats.min-1 in T3, P < 0.01]. Moreover, BPa increased at the beginning of T1 but was lower than in T2 and T3 [+9.3 (SEM 2.5) mmHg in T1, P < 0.05; +20.6 (SEM 2.6) mmHg and 26.5 (SEM 2.8) mmHg in T2 and T3, respectively, P < 0.01]. The rewarming during recovery was faster and higher in T1 compared to T2 and T3. These results showed that general and local physiological responses observed during an upper limb cold water test differed according to the area immersed. Index finger cooling led to earlier and faster CIVD without significant cardiovascular changes, whereas hand or forearm immersion led to a delayed and slower CIVD with a bradycardia at the end of the test.

Effects of different carbohydrate-electrolyte beverages on the appearance of ingested deuterium in body fluids during moderate exercise by humans in the heat.

To determine whether different forms of glucose (free and polymer) associated with sodium chloride influence the rate of water absorption during exercise in the heat, six men took part in five trials. Each trial included a passive heating session which resulted in a 2% loss of body mass, followed by 1h of treadmill exercise (at 50% of maximal oxygen uptake) in warm conditions (dry bulb temperature 35 degrees C, relative humidity 20%-30%). Immediately before exercise, the subjects were given either no fluid or a volume equal to 50% of the fluid previously lost (about 650 ml), chosen from among four D2O-labelled beverages: mineral water, a 6% glucose-electrolyte solution (GS), a 6% maltodextrin solution and a 6% maltodextrin-electrolyte solution. No significant differences were observed among these various beverages so far as temporal accumulation of deuterium in plasma, sweat and urine was concerned. During GS, the plasma volume was completely restored and the drifts of heart rate and rectal temperature were less marked than during other trials. These results would suggest that rehydration with GS was more efficient, probably because of an internal redistribution of water. The proportion of ingested water was twice as high in sweat as it was in urine. These findings may reflect the essential part played by circulatory adjustments in the transfer of plasma water into sweat and urine.

General and local cold responses in humans after 2 weeks at high altitude.

To investigate the effects of a short-term high altitude residence (2 weeks between 4150 m and 6885 m in the Andes) on the general and local cold responses after descent, 11 subjects were submitted both to a whole body standard cold air test (SCAT, dry bulb temperature = 1 degree C, 2 h, nude, at rest) and to a local cold water test of the right upper limb (CWT, 5 degrees C, 5 min) both before and after the expedition. Compared to before the expedition, a lower systolic blood pressure was observed after the high altitude residence [130.00 (SEM 3.35) mm Hg vs 140.40 (SEM 4.74) mm Hg at the end of CWT, P < 0.05] whereas no significant change either in diastolic blood pressure or in heart rate was found. All skin temperatures of the right upper limb were lowered (P < 0.05). During SCAT, body temperatures were unchanged (rectal and mean skin temperature, Tsk) but metabolic heat production was slightly but significantly diminished [110 (SEM 4) W.m-2 vs 125 (SEM 3) W.m-2, P < 0.05] and heat debt increased [11.37 (SEM 1.11) kJ.kg-1 vs 9.30 (SEM 2.30) kJ.kg-1, P < 0.05]. Moreover, the time of onset of continuous shivering (d) was shortened [8.20 (SEM 1.90) min vs 17.30 (SEM 3.60) min, P < 0.05] and the level of Tsk observed at (d) was higher [25.70 (SEM 0.80) degrees C vs 23.57 (SEM 0.78) degrees C, P < 0.05] suggesting an increase in the sensitivity of the thermoregulatory system despite the slight decreased shivering activity observed. It was concluded that general and local cold tolerance were modified by a short-term residence at altitude and that the changes observed were not in accordance with general or (and) local cold adaptation. In contrast, high altitude sojourn could be a risk factor for frostbite of the extremities.

Effects of hydration state on hormonal and renal responses during moderate exercise in the heat.

The effects of hydromineral hormones and catecholamines on renal concentrating ability at different hydration states were examined in five male volunteers while they performed three trials. Each of these trials comprised a 60-min exercise bout on a treadmill (at 50% of maximal oxygen uptake) in a warm environment (dry bulb temperature, 35 degrees C; relative humidity, 20-30%). In one session, subjects were euhydrated before exercise (C). In the two other sessions, after thermal dehydration (loss of 3% body mass) which markedly reduced plasma volume (PV) and increased plasma osmolality (osm[pl]), the subjects exercised either not rehydrated (Dh) or rehydrated (Rh) by drinking 600 ml of mineral water before and 40 min after the onset of exercise. During exercise in the Dh compared to C state, plasma renin, aldosterone, arginine vasopressin (AVP), noradrenaline and adrenaline concentrations were increased (P < 0.05). A reduction in creatinine clearance and urine flow was also observed (P < 0.05) together with a decrease in urine osmolality, osmolar clearance and sodium excretion, while free water clearance increased (P < 0.05). However, compared to Dh, Rh partially restored PV and osm(pl) and induced a marked reduction in the time courses of both the plasma AVP and catecholamine responses (P < 0.05). Values for renal water and electrolyte excretion were intermediate between those of Dh and C. Plasma atrial natriuretic peptide presented similar changes whatever the hydration state. These results demonstrate that during moderate exercise in the heat, renal concentrating ability is paradoxically reduced by prior dehydration in spite of high plasma AVP levels, and might be the result of marked activation of the sympatho-adrenal system. Rehydration, by reducing this activation, could partially restore the renal concentrating ability despite the lowered plasma AVP.